The Cell Cycling and Signaling Program has continued to evolve and has now expanded to include active programs in epigenetics, stem cell biology and tumor microenvironment. This interdisciplinary Program focuses on the regulation of cell signaling and cell cycle control and how alterations in these processes modulate gene expression, cause mutations, and fuel multistep carcinogenesis. The cell cycle is the collection of biochemical networks whereby one cell gives rise to two. This entails the coordination of three fundamental programs: cell growth, cell metabolism and cell division. Cell division, the increase in cell number, encompasses the proper replication and segregation of the genetic material to two daughter cells. Cell growth, the increase in cell mass and components, must be coordinated with division to ensure proper cell size, function, and position. Superimposed on both of these fundamental programs is the differentiated status of the cell, ranging from stem cell to terminal differentiation. Program Members study regulated entry into the cell cycle, which include proper molecular controls, mechanisms for ensuring the fidelity of the processes, and responses to exogenous signals for growth and differentiation. Members also study exit from the cell cycle of both the reversible kind (checkpoint control, differentiation) and the irreversible kind (senescence and death). Although core components of the cell cycle machinery are common to all eukaryotic cells, the strategy of regulation is often specific to the organism, the tissue, the cell, or the physiological/differentiated state. Multiple aspects of these processes are often controlled by nuclear organization (both genetic and epigenetic) and by signals from the extra-cellular matrix (tumor microenvironment). Observations resulting from basic research in these fundamental processes are applied to clinical questions of diagnosis, prognosis, and prevention of disease and will ultimately translate into the design of better preventive and therapeutic strategies. This Program interacts with several organ specific programs for the purpose of applying these fundamental processes to specific neoplasias. Many Members also belong to organ-specific Programs to facilitate exchange. The Program has $18,544,836 Total peer reviewed support for the last budget year. The Program has 10% intra-programmatic and 25% interprogrammatic publications.